Rett Syndrome, Congenital Variant

A number sign (#) is used with this entry because the congenital variant of Rett syndrome is caused by heterozygous mutation in the FOXG1 gene (164874) on chromosome 14q13.

Description

The congenital variant of Rett syndrome is a severe neurodevelopmental disorder with features of classic Rett syndrome (RTT; 312750), but earlier onset in the first months of life. Classic Rett syndrome shows later onset and is caused by mutation in the MECP2 gene (300005).

Clinical Features

Ariani et al. (2008) reported 2 unrelated girls, aged 22 years and 7 years, with a congenital variant of Rett syndrome. Both had normal birth, but developed progressive microcephaly at age 3 months. Both showed poor response early in life and were unable to lift their heads. Both also were apraxic and showed peculiar jerky movements of the upper limbs and midline stereotypic activities typical of classic Rett syndrome. Neither acquired spoken language, and both had EEG abnormalities with a multifocal pattern with spikes and sharp waves and occasional paroxysmal activity. Other features included corpus callosum hypoplasia, occasional abnormal breathing patterns, and bruxism.

Mencarelli et al. (2010) reported 4 unrelated girls, ranging in age from 3 to 13 years, with the congenital variant of Rett syndrome. All had hypotonia, unresponsiveness, and irritability in the neonatal period. At birth, head circumference was normal, but showed deceleration of growth soon after. Psychomotor regression became apparent between 3 and 6 months of age. Motor development was severely impaired, and hand use was absent. Typical stereotypic hand and mouth movements were present. All had severe mental retardation and poor eye contact, and none achieved walking or speech. Other features included abnormal movements of the tongue, jerky movements of the limbs, and seizures. Brain MRI showed hypoplasia of the corpus callosum. The older patients had severe scoliosis, kyphosis, genu valgum, pes planus, and spasticity.

Philippe et al. (2010) reported 2 unrelated females with the congenital variant of Rett syndrome. The first was a 22-year-old woman who was noted to have deceleration of head growth at age 2 months, followed by impaired social interaction consistent with autism. She later showed sleep disruption associated with EEG abnormalities, and never acquired speech or purposeful hand movements. Brain MRI showed hypoplasia of the corpus callosum with decreased white matter volume. The second patient was a 10-year-old girl who was noted to have delayed development at 6 months of age, followed by postnatal deceleration of head growth at 9 months. At age 5 years, she had repetitive stereotypic hand movements, absence of speech, and inappropriate laughter. At age 9 years, she had poor eye contact, ataxia, and drooling. Brain MRI did not reveal any malformations. Philippe et al. (2010) suggested that the second patient's phenotype could be compatible with a diagnosis of classic Rett syndrome, and suggested that individuals with classic Rett syndrome should also be tested for mutations in the FOXG1 gene.

Kortum et al. (2011) reported 11 patients with what they termed the 'FOXG1 syndrome,' and reviewed the phenotype of 15 previously reported patients. The disorder comprises mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies, and dyskinesias, such as dystonia, chorea, and athetosis. The patients also developed epilepsy after age 3 months and showed poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastroesophageal reflux. Brain imaging studies showed simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachygyria. Although the phenotype overlaps both classic and congenital Rett syndrome, Kortum et al. (2011) concluded that patients with FOXG1 mutations have a distinctive and clinically recognizable phenotype consistent with a developmental encephalopathy.

In a compilation of 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1, Mitter et al. (2018) observed that primary microcephaly was reported in 24%.

Genotype/Phenotype Correlations

Mitter et al. (2018) reviewed the genotype-phenotype correlation in 83 patients with mutations in FOXG1. They found that distinct genotype-phenotype associations could be delineated for 5 different FOXG1 genotype groups. The most severe phenotypes were found in patients with FOXG1 frameshift or nonsense variants in the N-terminal domain and the forkhead domain, except in conserved site 1. Most children with mutations in those 2 domains did not achieve unassisted sitting or walking and were not able to use their hands purposefully. In comparison, significantly milder phenotypes were associated with FOXG1 missense variants in the forkhead conserved site.

Inheritance

Almost all cases of the congenital variant of Rett syndrome have occurred sporadically as a result of de novo mutation in the FOXG1 gene. Diebold et al. (2014) reported a 2-year-old boy with delayed psychomotor development, poor growth, microcephaly, lack of speech, hypotonia, seizures, dyskinesia, and cerebral atrophy associated with a heterozygous truncating mutation in FOXG1. The mutation was absent from the father's DNA, but was present at low levels in the mother's DNA, consistent with somatic mosaicism. Detailed analysis showed the mutation in 35.6% of maternal leukocytes and 9.7% of her fibroblasts. Diebold et al. (2014) noted the implications for genetic counseling.

In the cohort of 83 patients described by Mitter et al. (2018), 5% of the families (4/76) had more than 1 affected child with a FOXG1 variant (excluding identical twins). In only 1 of 3 previously described families with several affected children, maternal somatic mosaicism for the FOXG1 likely pathogenic variant was documented. The parents of the patients in these families were reported as unaffected. Therefore, in genetic counseling of parents of a patient with an apparent de novo variant, gonadal mosaicism should be considered, and prenatal genetic testing should be offered in all pregnancies.

Cytogenetics

Jacob et al. (2009) reported a 3-year-old girl with the congenital variant of Rett syndrome associated with a heterozygous de novo 2.5-Mb deletion of chromosome 14q12 including the FOXG1 gene and the C14ORF23 gene. She had microcephaly and onset of symptoms at birth with no evidence of regression. Severely delayed psychomotor development was noted at 4 months of age, and she could not sit, roll, crawl, or speak at age 16 months. She developed refractory complex partial and myoclonic seizures at age 11 months. Behavioral abnormalities included poor eye contact, stereotypic hand movements, bruxism, and nighttime screaming episodes. Other features included mildly dysmorphic facies, such as synophrys and depressed nasal bridge, constipation, gastroesophageal reflux, choreoathetoid movements, hyperreflexia, and hypotonia. Brain MRI showed normal structure.

In 7 unrelated patients with mental retardation who were referred for genomewide array CGH analysis, Brunetti-Pierri et al. (2011) identified 7 different but overlapping duplications of chromosome 14q12. The duplications ranged in size from 3 to 14 Mb and the minimal common duplicated region included 3 genes: FOXG1, C14ORF32, and PRKD1 (605435). All patients had developmental delay, mental retardation, and absent or delayed speech, and 4 had infantile spasms or other seizures, including 2 with hypsarrhythmia. Otherwise, the features were highly variable, and although 4 had dysmorphic features, there was no recognizable pattern. Brunetti-Pierri et al. (2011) concluded that increased dosage of FOXG1 was the best candidate to explain the neurodevelopmental phenotypes in these patients.

Tohyama et al. (2011) reported a Japanese girl who developed infantile seizures and spasms at age 4 months with progression to hypsarrhythmia. Treatment with adrenocorticotropic hormone resulted in seizure control by age 6 months, but she had mild psychomotor delay and poor speech at age 6 years. Chromosome analysis revealed mosaicism for maternal uniparental disomy of chromosome 14q. Microarray-based CGH delineated an 11.2-Mb duplication of 14q11.2-q12, which contained 124 genes, including the FOXG1 gene. Tohyama et al. (2011) concluded that increased dosage of the FOXG1 gene was responsible for the phenotype.

Molecular Genetics

In 2 unrelated girls with a congenital variant of Rett syndrome, Ariani et al. (2008) identified heterozygous truncating mutations in the FOXG1 gene (164874.0001 and 164874.0002).

Mencarelli et al. (2010) identified 4 different de novo heterozygous mutations in the FOXG1 gene (see, e.g., 164874.0003-164874.0004) in 4 unrelated girls with the congenital variant of Rett syndrome.

Philippe et al. (2010) identified 2 different de novo heterozygous mutations in the FOXG1 gene (164874.0005 and 164874.0006) in 2 unrelated females with the congenital variant of Rett syndrome.

Kortum et al. (2011) identified heterozygous deletions or mutations in the FOXG1 gene in 11 of 210 patients with severe mental retardation, microcephaly, and/or brain abnormalities. One known mutation (164874.0007) was identified in 2 patients, and 9 novel mutations, including 2 large deletions, a balanced translocation and a deletion that both may have disrupted/displaced putative cis-regulatory elements of FOXG1, and 5 sequence changes, were identified. All mutations that could be evaluated were of de novo origin.